It is known that the (S)-(+)-SAMe ion is highly unstable and consequently rapidly degradable if extracted from the producing cells. In fact, many years passed between the discovery of SAMe (Cantoni et al. “Phosphorous metabolism”, Baltimore 1952 2, 129; Cantoni et al. J. Biol. Chem, 1953, 204, 403) and its marketing. The stability problem was initially solved by salification, in particular in the form of sulphates. However, the sulphate salts of SAMe sometimes cause side effects, especially in the gastric mucosa, due to their inherent acidity.
It is known that (R, S) SAMe is a physiological donor of methyl groups involved in enzymatic reactions of transmethylation, which is present in all living organisms and has therapeutic effects on chronic liver disorders, adiposis, lipaemia and atherosclerosis.
It is also known (J. W. Cornforth, J.A.C.S., 1977, 99, 7292-7300; Stolowitz et al., J.A.C.S., 1981, 103, 6015-6019) that products containing (R, S) SAMe consist of a mixture of two diastereoisomers: (R)-(+)-SAMe and (S)-(+)-SAMe, which have the following molecular structure:

It has also been demonstrated (De La Haba et al., J.A.C.S. 1959, 81, 3975-3980) that only one of the two diastereoisomers, ie. (S)-(+)-SAMe, is enzymatically active by spontaneous transmethylation and racemisation, and consequently generates the formation of the inactive diastereoisomer (R)-(+)-SAMe amounting to approx. 20% (Wu et al., Biochemistry 1983, 22, 2828-2832).
It has been observed that in all the products available on the market containing SAMe, the inactive diastereoisomer (R)-(+)-SAMe is present in the amount of at least 20%; it has further been observed that said percentages increase over time to 40% and more due to spontaneous racemisation.
The cells have a natural content of (S)-(+)-SAMe equal to approx. 100%, but the industrial extraction and purification methodology produces a partly degraded product, and consequently a mixture of ≧20% (R)-(+)-SAMe and ≦0.80% (S)-(+)-SAMe
These factors clearly confirm that the mixture of diastereoisomers is unstable over time, and this was already known in relation to the product in solution (G. L. Creason et al., Phytochemistry, vol. 24, N. 6, 1151-1155, 1985; H. C. Uzar, Liebigs Ann. Chem. 1989, 607-610).
It has also been observed that (R, S) SAMe, and its salified forms approved for pharmaceutical use, present problems of instability, in addition to the complexity of the preparation and purification processes.
Known purification processes involve the use of strong acid resins (JP 13680/1971), chelating resins (JP 20998/1978) or expensive special reagents, such as picric or picolinic acid (U.S. Pat. No. 3,707,536 and U.S. Pat. No. 3,954,726); however, they lead to partial racemisation of the SAMe sulphur and consequently to the production of end products containing the inactive diastereoisomer in an amount exceeding 20%.
However, purification processes involving the use of weak acid resins (JP 14299/1981, FR-A-2531714, EP-A-0141914) only allow partial separation of the active diastereoisomer to be obtained, and consequently a degree of purity insufficient for pharmaceutical purposes.
Although the performance of some of the said processes allows greater purity to be obtained, partial racemisation implies, in any event, that at least 20% of inactive diastereoisomer is present; moreover, in some cases (FR 2531714), potassium bicarbonate is used to extract the product from the cells, with consequent precipitation of potassium perchlorate, which causes difficulty with the separation and subsequent elimination of the product. In EP-A-0141914, the lysis of yeast cells containing SAMe is performed in the presence of an organic solvent (such as ethyl acetate, acetone, etc.), also using chromatographic columns which require the use of resins with a particle size of 100-200 mesh, involving heavy investments and maintenance costs for regeneration and washing.
The use of solvents to extract the SAMe necessarily involves the use of flameproof plant, solvent recovery and distillation systems, as well as the separation and necessary drying of the depleted biomass, to prevent it from being eliminated together with the residual solvent. All these factors clearly involve an increase in expenditure and the cost of the operations.
Morana et al., Biochimica Biophysica Acta, 1573 (2002), 105-108, disclose that SAMe may be stabilized by trehalose in lyophilized yeast extracts and, to a lesser extent, in lyophilized yeast cells. Lyophilization is however disadvantageous since the cells are subjected to stressful conditions (frozen at −20° C. and then thawed at 37° C.) and trehalose is anyhow presumed essential to stabilize intracellular SAMe. The addition of trehalose would moreover involve economical and regulatory problems.
There is consequently a need for derivatives or dosage forms of SAMe wherein the percentage of active (S)-(+)-SAMe diastereoisomer is clearly higher than the inactive (R)-(+)-SAMe isomer, and wherein the said percentage is stable over time. A further important goal would be a stable administration dosage form cf (S)-(+)-SAMe as a free base, without recurring to the formation of salts and/or to stabilizing agents and without subjecting yeast cells to stressful conditions.